Irritable bowel syndrome (IBS) affects up to 15% of the U.S. population, produces significant negative effects on quality of life, work productivity and significant health care costs. IBS is defined by the occurrence of intermittent periods of abdominal pain and altered bowel habits and the absence of observable biological abnormalities. Although no pathogenic mechanisms have been defined, human studies demonstrate that IBS is associated with a state of chronic visceral hypersensitivity. The mechanisms responsible for the generation and maintenance of visceral hypersensitivity in IBS patients are not known. We have developed a rat model initiated by a noxious stimulus delivered to the colon of neonatal rats that result in long-lasting visceral sensitization. As adults (8-12 weeks), these rats display an increased sensitivity to colorectal distention, increased excitability of extrinsic colon-specific sensory neurons, and gene plasticity in the S1 dorsal root ganglia. These changes occur in the absence of histological evidence of inflammation or other anatomical abnormalities and suggest a reprogramming of nociceptive signaling characteristic of peripheral sensitization. This proposal will evaluate the contributions of TRPV1 and p38 and ERK MAPK to the development of peripheral sensitization in this model. TRPV1 is a cation channel expressed on the majority of nociceptive sensory afferents that is activated by acid and various noxious and inflammatory stimuli. Our preliminary results show that antagonism of TRPV1 prior to neonatal administration of acetic acid attenuates the development of the persistent sensitivity to colorectal distention. We also show that neonatal acetic acid treatment activates p38 and ERK MAP kinases in DRG containing the soma of colon afferents. We hypothesize that TRPV1 activation by acetic acid in neonatal sensory neurons produces increased excitability and changes in gene expression in colon DRG neurons via activation of the ERK 1/2 and p38 MAPK pathways. This hypothesis will be tested using a behavioral assay for visceral sensitivity, patch clamp studies on isolated colon DRG neurons, gene expression analysis by quantitative RT-PCR, western blot and immunofluorescence studies. Our long-term objective is to identify key molecular events responsible for the initiation and perpetuation of the sensitized state in IBS and provide targets for new pharmacological approaches for the treatment of this syndrome. [unreadable] [unreadable] [unreadable]